Document Detail


Interpreting cell cycle effects of drugs: the case of melphalan.
MedLine Citation:
PMID:  16195878     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Multiple effects usually occur in the cell cycle, during and after the exposure to a drug, while treated cells flowing through the cycle encounter G1, S and G2M checkpoints. We developed a simulation tool connecting the microscopic level of the cellular response in G1, S and G2M with the experimental data of growth inhibition and flow cytometry. We found that multiple-often not intuitive-combinations of cytostatic and cytotoxic effects can be in keeping with the observations. This multiplicity of interpretation can be strongly reduced by considering together data with different methods, ideally reaching a reconstruction of the underlying cell cycle perturbations. Here, we propose an experimental plan including a time course of DNA flow cytometry and absolute cell count measurements with several drug concentrations and a limited number of flow cytometric DNA-Bromodeoxyuridine and TUNEL analyses, coupled with computer simulation. We showed its use in the attempt to define the complete time course of the effects of melphalan on three cancer cell lines. After drug treatment, each subset of cells experienced blocks and lethality in all phases of the cell cycle, but the dynamics was different, the differences being strongly dose-dependent. Our approach allows a better appreciation of the complexity of the cell cycle phenomena associated with drug treatment. It is expected that such level of understanding of the time- and dose-dependence of the cytostatic and cytotoxic effects of a drug might support rational therapeutic design.
Authors:
Monica Lupi; Paolo Cappella; Giada Matera; Claudia Natoli; Paolo Ubezio
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-09-30
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  57     ISSN:  0344-5704     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-01-11     Completed Date:  2006-03-16     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  443-57     Citation Subset:  IM    
Affiliation:
Biophysics Unit, Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157, Milano, Italy. ubezio@marionegri.it
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites, Antineoplastic / metabolism
Antineoplastic Agents, Alkylating / pharmacology*
Bromodeoxyuridine / metabolism
Cell Cycle / drug effects*
Cell Death / drug effects
Cell Division / drug effects
Cell Line, Tumor
Computer Simulation
DNA, Neoplasm / chemistry,  metabolism
Dose-Response Relationship, Drug
Flow Cytometry
Fluorescein-5-isothiocyanate
G1 Phase / drug effects
G2 Phase / drug effects
Humans
In Situ Nick-End Labeling
Kinetics
Melphalan / pharmacology*
S Phase / drug effects
Time Factors
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Antineoplastic Agents, Alkylating; 0/DNA, Neoplasm; 148-82-3/Melphalan; 3326-32-7/Fluorescein-5-isothiocyanate; 59-14-3/Bromodeoxyuridine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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